Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

Abstract

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody–drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development.

Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models

“…Several ADCs have the ability to induce both direct cytotoxic effects as well as ICD as part of their mechanisms of action ( 2 ) and, given the link between UPR activation and ICD ( 35 ), we next sought to determine if HDP-101 could so as well. Starting with the MM1.S cell model, isotype antibody or HDP-101-treated cells were analyzed to detect externalization of Calreticulin (CRT) or High mobility group box 1 (HMGB1) by immunofluorescence.…”

“…ADCs with microtubule-targeting agents such as BelaMaf’s auristatins work well against proliferating cells ( 2 ) while amanitins can target quiescent cells ( 25 ), and may thus have an advantage against hypo-proliferative tumors like myeloma, as well as against myeloma-initiating or stem-like cells. The latter was supported by our studies of ALDH-positive clonogenic cells (Fig.…”

“…These have added to the effectiveness of older therapeutics such as corticosteroids and alkylating agents, and use of these drugs in rational combination regimens has substantially improved long-term outcomes. Encouragingly, this trend seems likely to continue with the development of novel immunotherapeutics that work through various mechanisms of action, including antibody drug conjugates (ADCs)( 2 ), T-cell engaging bispecific antibodies ( 3 ), and chimeric antigen receptor (CAR)-guided T-cells ( 4 ). B-cell maturation antigen (BCMA) has been an especially popular target for these drugs since it is commonly and fairly specifically expressed on plasma cells, and plays an important role in plasma cell differentiation ( 5 ).…”

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma

“…MM is the second most common hematologic malignancy, and its incidence is elevated in the aging population [3]. The current standard therapies for MM, such as proteasome inhibitors, immunomodulatory drugs, and anti-CD38 targeting drugs, have limited effectiveness [4], but newer therapies, including B cell maturation antigen (BCMA)-targeted antibody-drug conjugates (ADCs) [5,6], T-cell-redirecting bispecific antibodies (TCBs) [7,8], and chimeric antigen receptor T cell (CAR-T) therapies [9][10][11], have shown encouraging results in recent years [12]. Although BCMA is expressed in most malignant plasma cells, its expression is heterogeneous.…”

CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts

“…The most advanced ADC in MM was belantamab mafadotin, which also targets BCMA and received accelerated FDA approval. Unfortunately, this was later withdrawn due to its modest clinical benefits and ocular toxicities [12,13]. Still, the use of ADCs targeting alternative antigens besides BCMA may be a useful way to avoid cross-resistance in patients relapsing after CAR-T and bispecific antibodies.…”